The proposed research is designed to gain a better understanding of the regulation of central nervous system (CNS) acid-base and electrolyte homeostasis. The CNS acid-base status, in turn, has an important effect on the central chemical ventilatory drive. In studies of regulation of [HCO3-] in the CNS, our preliminary data show that active regulation of cerebrospinal fluid (CSF) [Cl-] is critical to establishing the level of [HCO3-]. Regulation of the CSF [Cl-] concentration thus plays a key role in CNS acid-base homeostatis, yet the mechanisms underlying its control remain uncertain. The role of net flux of chloride will be evaluated by studying the CSF electrolyte and acid-base composition following administration of chloride transport inhibitors and/or acid-base disturbances in anesthetized dogs. Quantitative estimates of the individual unindirectional fluxes of radiolabelled chloride between blood, CSF, brain ECF in anesthetized dogs will be made. The use of 38 Cl-, a short half-lived isotope, will allow multiple studies to be performed in a given animal, permitting each animal to serve as its own control. By studying the effects of chloride transport inhibitors and acid-base disturbances on unidirectional fluxes, as well as on the CSF electrolyte and acid-base status, and good understanding of the role of chloride movements in CNS acid-base regulation will be gained. Brain intracellular acid-base and high-energy phosphate metabolism and their relation to ventilation will be evaluated in unanesthetized rats. Thirty one phosphorus (31P) nuclear magnetic resonance (NMR) spectroscopy will be used to measure brain intracellular pH, ATP, and phosphocreatine levels. NMR allows both steady and nonsteady state noninvasive measurements of these variables simultaneously, in the intact, unanesthetized animal. Alterations of inspired CO2, O2 and changes in systemic chloride concentration will induce CNS acid-base stress. In this way, the intracellular homeostatic mechanisms will be evaluated. Thirteen carbon (13C) NMR will be used to follow intracellular CO2 metabolism. These studies will provide a basis for the non-invasive measurement of intracellular adaptations to acid-base stress and the relation between brain intracellular events and ventilation.